Hepatitis C virus in India: Challenges and Successes

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Abbreviations

ASV

asunaprevir

BOC

boceprevir

CHC

chronic hepatitis C

COVID‐19

coronavirus disease 2019

DAA

direct‐acting antiviral

DCV

daclatasvir

DSV

dasabuvir

EBR

elbasvir

GZR

grazoprevir

HBV

hepatitis B virus

HCV

hepatitis C virus

HIV

human immunodeficiency virus

ITT

intention to treat

LDV

ledipasvir

NAT

nucleic acid amplification test

NVHCP

National Viral Hepatitis Control Program

OBV

ombitasvir

Peg‐IFN

pegylated interferon

PTV/r

paritaprevir/ritonavir

RBV

ribavirin

SIM

simeprevir

SOF

sofosbuvir

SVR

sustained virological response

TRV

telaprevir

VEL

velpatasvir

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The past decade has seen a paradigm shift in the management of hepatitis C virus (HCV) infection with the development of direct‐acting antiviral (DAA) drugs. In 2016, the World Health Organization laid out the Global Health Sector Strategy on viral hepatitis, which endorsed the elimination of viral hepatitis by 2030. In a country like India with a large population and diverse socioeconomic status and cultural practices, the path to HCV elimination has indeed thrown up both challenges and success stories.

Challenges

Estimating the Disease Burden

According to global estimates, the prevalence rate of HCV viremia in India in 2015 was 0.5%, affecting about 4.7 to 10.9 million people. ¹ In a meta‐analysis of 327 studies, the prevalence rate of HCV in India, as estimated by the seropositive rates of anti‐HCV antibody, was 0.85% in community studies, 0.44% in asymptomatic blood donors, and 0.88% in pregnant women. ² The community‐based prevalence results were available from only three states in the country and were associated with marked heterogeneity; therefore, they may not truly reflect the nationwide prevalence. Similarly, the prevalence rates of anti‐HCV positivity among blood donors varied between 0.11% and 1.24% across different states (Fig. 1). Notwithstanding the limitations, in a country with more than 1.3 billion individuals, this suggests a huge burden of disease.

Screening High‐Risk Individuals

In contrast with the community prevalence, high‐risk individuals, including patients with human immunodeficiency virus (HIV) infection, patients receiving hemodialysis, intravenous drug users, patients requiring multiple blood transfusion, individuals with high‐risk sexual behavior, and attendees of sexually transmitted disease clinics, have a high prevalence of HCV ranging from 3.5% to 44.7%. In a meta‐analysis of 30 studies, the pooled prevalence rate of HCV and hepatitis B virus (HBV) coinfection was 1.89% in India. ³ The prevalence rate of antibodies to HCV ranged between 7.2% and 76.6% in patients with HIV. Integration of HCV testing into existing programs catering to those at high risk (e.g., those with HIV) has shown an increase in the identification and treatment of such patients. ⁴ Hence it is imperative to implement HCV infection screening in these diverse high‐risk groups and integrate HCV testing in patients with HIV or HBV infections. Data on modes of transmission are also scarce, but policies regarding the safe use of blood products and safe injection practices have been implemented to break the transmission chain. Testing all blood donors for HCV was made mandatory by the Government of India in June 2001. Nucleic acid amplification tests (NATs) are highly sensitive and specific for the detection of HCV among blood donors, albeit costly. Until 2017, barely 2% of the blood banks in India had facilities for NATs, and limited results showed HCV positivity rates of 1 in about 5400 seronegative samples. ⁵ It is indeed warranted to expand this testing facility and ensure more widespread application across the country.

HCV Genotypes, Drug Availability, and Cost

In India, HCV genotype 3 is the predominant genotype as compared with genotype 1 in the West. ⁶ All‐cause mortality, progression to cirrhosis, and development of hepatocellular cancer are highest in patients with genotype 3. ⁷

Of all available DAAs, only four are available in India: sofosbuvir (SOF), velpatasvir (VEL), ledipasvir (LDV), and daclatasvir (DCV). This limits our armamentarium for treating those with prior DAA failure, cirrhosis and genotype 3, or resistance‐associated substitutions. The availability of pangenotypic drugs has obviated the need for genotype testing outside research settings. However, the total cost of HCV‐RNA testing and 12‐week therapy costs about $250 to $300, which is still prohibitive for many patients. Widespread, rapid, and cheap availability of HCV‐RNA testing and a cost‐effective mechanism to provide uninterrupted free drugs are essential if we aim to reach the elimination target by 2030.

Ensuring Compliance to Therapy

Past experience from other national programs, such as the National Tuberculosis Elimination Program, has shown that about 15% of patients default despite free treatment. ⁸ A proportion of patients with HCV infection may be asymptomatic and incidentally detected on screening. Ensuring compliance to therapy, therefore, becomes challenging. Patients with HCV‐related cirrhosis need a more comprehensive evaluation than just DAA therapy. In addition to providing free medications, we also need effective mechanisms for monitoring adherence, testing for treatment response, management of cirrhosis and its complications, and hepatocellular cancer screening at the community level.

Effect of COVID‐19 Infection

The coronavirus disease 2019 (COVID‐19) pandemic affected health care services worldwide. It is estimated that 1‐year delay in HCV treatment programs would result in more than 72,000 deaths. ⁹ Despite the lack of published data from India, it is reasonable to assume that strict lockdown, travel restrictions, and diversion of hospital services to patients with COVID infections would have impacted the treatment of patients with HCV infection.

Successes

National Viral Hepatitis Control Program

The Government of India launched the National Viral Hepatitis Control Program (NVHCP) in 2018 with the aim to prevent and treat viral hepatitis (hepatitis A, B, C, and E) and provide screening, diagnosis, treatment, and counseling services free of cost to all. The NVHCP synergizes with other national programs, such as the National AIDS Control Program, to promote safe blood and blood products, preventive services for the high‐risk population, and injection safety practices. Therefore, an integrated approach will lead to better utilization of resources, promote screening and early treatment, and prevent attrition.

Advantages of Generic DAAs

The availability of generic DAAs has reduced the cost of therapy and has shown excellent results with 12‐week posttreatment virological suppression rates (Table 1). ⁶ Treatment with generic DAAs increases life expectancy by about 8 years, and the treatment becomes cost‐effective within 2 years. ¹⁰

TABLE 1.

SVR‐12 Rates Using Generic DAAs in India

Study	N	Location	Population	Drug Used	SVR‐12 Rates
Dhiman et al. 11	48,088	Punjab	Treatment naive/experienced	SOF + DCV/LDV ± RBV	91.2% (modified ITT)
			CHC/compensated cirrhosis		91.6% (per protocol)
Gupta et al. 6	490	New Delhi	Treatment naive/experienced	SOF + DCV/LDV ± RBV	95.90%
			CHC/compensated/decompensated cirrhosis	Peg‐IFN + SOF + RBV
Sood et al. 13	129	Multicenter	Treatment naive/experienced	SOF + VEL	93.00%
			CHC/compensated cirrhosis
Tang et al. 14	66	Mumbai	Treatment naive/experienced	SOF + RBV (generic and nongeneric)	72.4% (generic), 75.7% (nongeneric)
			CHC/compensated/decompensated cirrhosis
Sood et al. 15	736	Punjab	Treatment naive	SOF + RBV ± Peg‐IFN	95.80%
			CHC/compensated/decompensated cirrhosis
Sidhu et al. 16	931	Multicenter	Treatment naive/experienced	SOF + RBV ± Peg‐IFN	91% (without RBV)
			CHC/compensated cirrhosis		92% (with RBV)
Mehta et al. 17	648	Punjab	Treatment naive/experienced	SOF + DCV/LDV ± RBV	98.1% (modified ITT)
			CHC/compensated/decompensated cirrhosis		88.1% (ITT)

Decentralized Care Models

Extension for health care outcomes is a novel model for collaboration between specialists and primary care physicians in rural areas. A decentralized care hub‐and‐spoke model was implemented in Punjab, the state with the highest seroprevalence of HCV in India. Using an algorithm‐based treatment with generic DAA combined with fortnightly supervision by telehealth clinics, more than 48,000 patients with HCV received medication, of which 91.2% of patients achieved sustained virological response (SVR) at 12 weeks posttherapy (SVR‐12). ¹¹ These results are comparable with those from academic centers and other real‐world cohorts (Tables 1 and 2). In a meta‐analysis of studies estimating treatment outcomes of decentralized HCV care, the pooled SVR‐12 was 81% on intention‐to‐treat (ITT) analysis. ¹² It further affirms this model’s utility in providing the standard of care using a decentralized model with the existing public health infrastructure.

TABLE 2.

Real‐World Results of HCV Treatment Strategies

Study	N	Country	Population	Genotype	Drug Used	Overall SVR‐12 Rates
Dhiman et al. 11	48,088	India	Treatment naive/experienced	All	SOF + DCV/LDV ± RBV	91.2% (modified ITT)
			CHC/compensated/decompensated cirrhosis			91.6% (per protocol)
Ioannou et al. 18	17,487	United States	Treatment naive/experienced	1‐4	DAA ± Peg‐IFN ± RBV (SOF, LDV, OBV, PTV/r, DSV in any combination)	92.80%
			CHC/compensated/decompensated cirrhosis
Calleja et al. 19	1567	Spain	Treatment naive/experienced	1	OMV + PTV/r + DSV ± RBV	96.80%
	1758		CHC/compensated/decompensated cirrhosis		LDV/SOF ± RBV	95.80%
Höner Zu Siederdissen et al. 20	6606	Germany	Treatment naive/experienced	1	DAA ± Peg‐IFN ± RBV (SOF, TRV, BOC, SIM, DCV, LDV, OBV, PTV/r, DSV in any combination)	92%
			CHC/compensated/decompensated cirrhosis
Haridy et al. 21	1909	Australia	Treatment naive/experienced	All	DAA ± RBV (SOF, LDV, DCV, EBR, GZR, OBV, PTV/r, DSV in any combination)	80.4% (overall)
			CHC/compensated/decompensated cirrhosis			95.7% (completing treatment)
Gupta et al. 22	300	Rwanda	Treatment naive/experienced	1, 4	SOF + LDV	87%
			CHC/compensated cirrhosis
de Oliveira Lobato et al. 23	3939	Brazil	Treatment naive/experienced	All	DAA ± Peg‐IFN ± RBV (SOF, DCV, LDV, SIM, OBV, PTV/r, DSV in any combination)	96%
			CHC/compensated/decompensated cirrhosis
Hong et al. 24	400	Taiwan	Treatment naive/experienced	1, 2	DAA ± RBV (SOF, DCV, LDV, ASV, EBR, GZR, OBV, PTV/r, DSV in any combination)	85%‐100% (depending on the regimen)
			CHC/compensated cirrhosis

Conclusions and Future Directions

HCV elimination in India by 2030 is difficult but possible. Contributions from multiple stakeholders are warranted. In addition to the government policies and financial allocation for drug availability, testing kits, and operational expenditures, we also require media support for creating awareness among the common public regarding preventive and treatment options for HCV. The success of the decentralized model has shown that it can be applied in other areas of the country. Although the entire focus of the country is presently diverted to management of the COVID‐19 pandemic, it is imperative that HCV treatment not be ignored. Continuing services through the NVHCP and teleconsultation‐based regular patient follow‐up are measures that can enable uninterrupted care. We still have a long way to go, but we have taken small steps in the right direction.

FIG 1.

(A) HCV prevalence in asymptomatic blood donors in India. (B) HCV prevalence in patients infected with HIV in India.